Formoterol tartrate process and polymorph

ABSTRACT

A method of preparation of a highly pure salt of R,R-formoterol L-tartrate is disclosed. The process provides the most thermodynamically stable polymorph by recrystallization of a novel polymorph.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 12/329,196,filed Dec. 5, 2008, which was a divisional of application Ser. No.12/013,848, filed Jan. 14, 2008, now U.S. Pat. No. 7,479,572, which wasa divisional of application Ser. No. 11/462,637, filed Aug. 4, 2006, nowU.S. Pat. No. 7,342,132, which was a continuation of application Ser.No. 11/052,268, filed Feb. 7, 2005, now U.S. Pat. No. 7,145,036, whichwas a continuation of application Ser. No. 10/806,993, filed Mar. 23,2004, now abandoned, which was a continuation of application Ser. No.10/238,204, filed Sep. 10, 2002, now U.S. Pat. No. 6,720,453, which wasa continuation of application Ser. No. 10/037,183, filed Nov. 9, 2001,now U.S. Pat. No. 6,472,563. The entire disclosures of all areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a method of preparation of a highlypure salt of optically pure formoterol and to a polymorph thereof.

BACKGROUND OF THE INVENTION

Formoterol, whose chemical name is(+/−)N-[2-hydroxy-5-[1-hydroxy-2[[2-(p-methoxyphenyl)-2-propyl]amino]ethyl]phenyl]-formamide,is a highly potent and ∃₂-selective adrenoceptor agonist having a longlasting bronchodilating effect when inhaled. The structure of formoterolis as shown:

Formoterol has two chiral centers in the molecule, each of which canexist in two possible configurations. This gives rise to fourcombinations: (R,R), (S,S), (R,S) and (S,R). (R,R) and (S,S) are mirrorimages of each other and are therefore enantiomers; (R,S) and (S,R) aresimilarly an enantiomeric pair. The mirror images of (R,R) and (S,S) arenot, however, superimposable on (R,S) and (S,R), which arediastereomers. Formoterol is presently available commercially only as aracemic diastereomer, (R,R) plus (S,S) in a 1:1 ratio, and the genericname formoterol refers to this enantiomeric mixture. The racemic mixturethat is commercially available for administration is a dihydrate of thefumarate salt. The order of potency of the isomers is(R,R)>>(R,S)=(S,R)>(S,S), and the (R,R)-isomer is 1000-fold more potentthan the (S,S)-isomer. Administration of the pure (R,R)-isomer alsooffers an improved therapeutic ratio. U.S. Pat. No. 6,268,533 and PCTapplication WO 00/21487 disclose that the L-(+)-tartrate salt ofR,R-formoterol is unexpectedly superior to other salts ofR,R-formoterol, being easy to handle, pharmaceutically innocuous andnon-hygroscopic.

The polymorphic behavior of drugs can be of crucial importance inpharmacy and pharmacology. Polymorphs are, by definition, crystals ofthe same molecule having different physical properties as a result ofthe order of the molecules in the crystal lattice. The differences inphysical properties exhibited by polymorphs affect pharmaceuticalparameters such as storage stability, compressibility and density(important in formulation and product manufacturing), and dissolutionrates (an important factor in determining bio-availability). Differencesin stability can result from changes in chemical reactivity (e.g.differential oxidation, such that a dosage form discolors more rapidlywhen comprised of one polymorph than when comprised of anotherpolymorph) or mechanical changes (e.g. tablets crumble on storage as akinetically favored polymorph converts to thermodynamically more stablepolymorph) or both (e.g. tablets of one polymorph are more susceptibleto breakdown at high humidity). As a result of solubility/dissolutiondifferences, in the extreme case, some polymorphic transitions mayresult in lack of potency or, at the other extreme, toxicity. Inaddition, the physical properties of the crystal may be important inprocessing: for example, one polymorph might be more likely to formsolvates or might be difficult to filter and wash free of impurities(i.e particle shape and size distribution might be different between onepolymorph relative to the other).

Each pharmaceutical compound has an optimal therapeutic bloodconcentration and a lethal concentration. The bio-availability of thecompound determines the dosage strength in the drug formulationnecessary to obtain the ideal blood level. If the drug can crystallizeas two or more polymorphs differing in bio-availability, the optimaldose will depend on the polymorph present in the formulation. Some drugsshow a narrow margin between therapeutic and lethal concentrations.Chloramphenicol-3-palmitate (CAPP), for example, is a broad spectrumantibiotic known to crystallize in at least three polymorphic forms andone amorphous form. The most stable form, A, is marketed. The differencein bio-activity between this polymorph and another form B, is a factorof eight—creating the possibility of fatal overdosages of the compoundif unwittingly administered as form B due to alterations duringprocessing and/or storage. Therefore, regulatory agencies, such as theUS Food and Drug Administration, have begun to place tight controls onthe polymorphic content of the active component in solid dosage forms.In general, for drugs that exist in polymorphic forms, if anything otherthan the pure, thermodynamically preferred polymorph is to be marketed,the regulatory agency will require batch-by-batch monitoring. Thus, itbecomes important for both medical and commercial reasons to produce andmarket the pure drug in its most thermodynamically stable polymorph,substantially free of other kinetically favored polymorphs.

U.S. Pat. No. 6,268,533, which is incorporated herein by reference,discloses that the L-(+)-tartrate salt of R,R-formoterol exists in twopolymorphic forms. We have now discovered a third polymorphic form of(R,R)-formoterol L-tartrate. As a result of its unique solubilityproperties, this third polymorph provides an opportunity for a greatlyimproved process for obtaining highly pure (R,R)-formoterol L-tartratein its most thermodyamically stable polymorphic form.

SUMMARY OF THE INVENTION

In one aspect the invention relates to (R,R)-formoterol L-tartrate inthe form of a crystalline solid comprising at least 95% of a polymorphhaving peaks at the diffraction degrees with the intensity shown belowin an X-ray powder diffraction pattern:

Polymorph C peak number 2-Theta Intensity 1 6.4 100.0 2 9.0 14.4 3 11.114.8 4 12.4 13.9 5 12.9 19.7 6 13.5 19.5 7 14.0 15.1 8 15.0 19.7 9 15.416.9 10 15.7 18.1 11 16.3 12.8 12 17.5 64.9 13 19.4 47.3 14 19.9 44.8 1521.3 29.3 16 22.3 31.5 17 22.9 35.8 18 24.1 80.0 19 24.7 17.6 20 25.511.3 21 26.0 15.6 22 26.8 9.1 23 27.4 8.5 24 28.4 10.8 25 29.0 8.5 2630.5 8.1 27 32.7 10.9 28 34.2 7.9 29 35.7 9.3 30 36.4 6.6 31 37.3 7.9 3237.8 9.1 33 39.3 10.1 34 39.6 11.4 35 41.1 5.7 36 42.3 4.7

Hence forth, this 36-peak polymorph, which has not been previouslydescribed in the literature, will be referred to as “polymorph C”.

In another aspect, the invention relates to a process for producing thisnew polymorph. The process comprises stirring a slurry of polymorph (B)in water, isopropyl alcohol and at least 13% by weight toluene at 40-55°C.

The discovery of polymorph C and its physical properties gives rise tothe third aspect of the invention: a process for the preparation ofhighly pure (R,R)-formoterol L-tartrate. In its most fundamentalembodiment, the process involves crystallizing polymorph C from aqueousisopropyl alcohol. This produces (R,R)-formoterol L-tartrate of achemical purity heretofore unattainable.

Another aspect of the invention, is then the (R,R)-formoterol L-tartrateproduced by this process. The (R,R)-formoterol L-tartrate resulting fromthe inventive process is in the form of a crystalline solid comprisingat least 95% of the most thermodynamically stable polymorph of(R,R)-formoterol L-tartrate. This polymorph, which will henceforth bereferred to as polymorph A, has 23 peaks at the diffraction degrees withthe intensity shown in the following X-ray powder diffraction pattern:

Polymorph A peak number 2-Theta Intensity 1 8.8 33.1 2 9.3 33.4 3 12.158.1 4 12.4 60.6 5 14.2 30.9 6 15.2 87.4 7 15.5 82.8 8 16.8 69.8 9 18.939.6 10 19.7 41.1 11 20.8 40.6 12 22.5 38.8 13 23.0 59.9 14 23.7 100.015 25.6 55.9 16 26.8 37.2 17 28.6 25.6 18 30.9 37.2 19 36.1 28.0 20 38.125.0 21 39.1 22.7 22 41.5 21.3 23 43.3 20.9

(R,R)-formoterol L-tartrate, predominantly in the polymorphic form A isknown and described in U.S. Pat. No. 6,268,533. However, even in itschemically purest state, the material described in the '533 patentcontains from 0.2 to 1.5% by weight of chemical impurities, one of whichis desformoterol L-tartrate. (R,R)-formoterol L-tartrate cannot bepurified to contain less than 0.2% by weight of any impurity, except bythe process of the instant application, employing the hitherto unknownpolymorph C.

In another aspect the invention relates to a method for preventingbronchoconstriction or inducing bronchodilation in a mammal byadministering the pure polymorph A. Pure, in the sense used herein,means containing less than 5% of other polymorphs of (R,R)-formoterolL-tartrate, less than 0.5% of other chemical impurities and less than 2%of other optical isomers of formoterol.

In another aspect the invention relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and pure polymorph A ofR,R-formoterol L-(+)-tartrate.

BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of the invention will become more readily apparent uponreference to the following description when taken in conjunction withthe accompanying drawings, in which:

FIG. 1 is an IR spectrum of R,R-formoterol L-(+)-tartrate, polymorph B.

FIG. 2 is a differential scanning calorimetric (DSC) trace ofR,R-formoterol L-(+)-tartrate, polymorph B.

FIG. 3 is an x-ray powder diffraction pattern (XRDP) trace ofR,R-formoterol L-(+)-tartrate, polymorph B.

FIG. 4 is an IR spectrum of R,R-formoterol L-(+)-tartrate, polymorph C.

FIG. 5 is a differential scanning calorimetric (DSC) trace ofR,R-formoterol L-(+)-tartrate, polymorph C.

FIG. 6 is an x-ray powder diffraction pattern (XRDP) trace ofR,R-formoterol L-(+)-tartrate, polymorph C.

FIG. 7 is an IR spectrum of R,R-formoterol L-(+)-tartrate, polymorph A.

FIG. 8 is a differential scanning calorimetric (DSC) trace ofR,R-formoterol L-(+)-tartrate, polymorph A.

FIG. 9 is an x-ray powder diffraction pattern (XRDP) trace ofR,R-formoterol L-(+)-tartrate, polymorph A.

DETAILED DESCRIPTION OF THE INVENTION

Two reports have been published describing the synthesis of all fourisomers of formoterol. In the first report [Murase et al. op. cit.], the(R,R)— and (S,S)-isomers were obtained by diastereomeric crystallizationof racemic formoterol with tartaric acid. In the second report [Trofastet al. op. cit.], racemic 4-benzyloxy-3-nitrostyrene oxide was coupledwith an optically pure (R,R)— or(S,S)—N-(1-phenylethyl)-N-(1-(p-methoxyphenyl)-2-propyl)amine to give adiastereomeric mixture of formoterol precursors, which were thenseparated by semipreparative HPLC and transformed to the pure formoterolisomers. Both syntheses suffer long synthetic procedure and low overallyield and are impractical for large scale production of optically pure(R,R)— or (S,S)-formoterol. For example, the Trofast reference describesreacting 4.5 grams of the styrene oxide with 4.8 grams of thephenethylamine to produce 94 milligrams of the pure S,S enantiomer. Theonly practical, economical and efficient method for synthesizingoptically pure formoterol is described in U.S. Pat. No. 6,268,533 andPCT application WO 00/21487. The synthesis is outlined in Scheme I:

This synthesis initially produces the kinetically favored polymorph,which will be referred to hereafter as polymorph B. Polymorph B exhibits30 peaks at the diffraction degrees with the intensity shown below in anX-ray powder diffraction pattern:

Polymorph B peak number 2-Theta Intensity 1 6.7 29.8 2 7.7 23.9 3 8.576.8 4 9.9 24.1 5 11.6 23.7 6 12.2 35.9 7 13.0 24.8 8 13.7 32.7 9 16.432.9 10 17.3 99.1 11 19.4 47.9 12 20.6 100.0 13 22.1 72.8 14 22.7 70.215 23.5 29.1 16 23.9 25.0 17 24.5 22.8 18 25.4 35.8 19 25.5 39.8 20 26.348.0 21 27.4 25.7 22 28.6 28.6 23 29.5 20.5 24 30.9 20.1 25 33.0 19.5 2637.2 22.1 27 38.6 20.1 28 40.9 19.7 29 41.7 20.0 30 44.3 20.0(R,R)-formoterol L-tartrate, in the polymorphic form B is known anddescribed in U.S. Pat. No. 6,268,533.

As the (R,R)-formoterol L-tartrate separates in the initialcrystallization from this process, it is predominantly in thekinetically favored form, polymorph B. Polymorph B is referred to in the'533 patent as P2. In pure form it exhibits a peak at about 179° C. ondifferential scanning calorimetry and is soluble in water at 25° C. tothe extent of 26.7 mg/mL. U.S. Pat. No. 6,268,533 describes theconversion of B to the thermodynamically most stable polymorphic form A.Polymorph A is referred to in the '533 patent as P1. Polymorph Aexhibits a peak at about 193° C. on differential scanning calorimetryand is soluble in water at 25° C. to the extent of 15.4 mg/mL. However,the product described in '533, as it initially crystallizes, containsfour identified chemical impurities (described below), and, no matterhow many times the product is recrystallized, the resulting polymorph Acontains at least 0.5% impurities. While not wishing to be held to anyparticular theory, applicants surmise that the conditions ofrecrystallization may result in the partial hydrolysis of the formamideto the amine:

Whatever the reason may be, the process described in the literaturecannot be made to produce (R,R)-formoterol L-tartrate polymorph Acontaining less than 0.5% impurities. The conundrum of purification wasalready recognized in U.S. Pat. No. 6,268,533, which states, “To obtain(R,R) formoterol L-tartrate of the highest chemical and optical purity,it is necessary that one not recrystallize P1 [polymorph A]. P1 is themore thermodynamically stable form and is preferred for formulations,but because of its lower solubility, it requires higher temperatures andlonger times to dissolve in the recrystallization solvent. As a result,some degradation occurs and impurities are introduced in therecrystallization process.”

A solution to the chemical purity problem has now been found. The answerlies in the existence and properties of a newly discovered thirdpolymorph, polymorph C.

In developing a process for production of (R,R)-formoterol L-tartrate asan active pharmaceutical ingredient (API), two factors are of greatimportance: the impurity profile and the crystal morphology of the API.The results from preliminary development work showed that the impurityprofile of the API consisted of impurities 7 and 8 whose abundancesranged from 0.2 to 1.5%, and that traditional crystallization methodscould not decrease the level of 7 below 0.2%. This preliminary work alsoindicated that the isolation and crystallization conditions yieldedperhaps as many as three polymorphic forms of the API. The requirementsfor the API necessitated levels of 7 and 8 below 0.2% and, as explainedabove, the API had to be in the most thermodynamically stable crystalform. The difficulty in controlling the level of 7 and the polymorphicnature of the API required the development of a process for theproduction of (R,R)-formoterol L-tartrate to provide the requisitepurity and the proper crystal form.

Initial studies characterized the impurity profile of isolatedintermediates and the API at various stages in the process. As shown inScheme 1, the crude product was isolated as the tartrate salt from afour step process that entailed epoxide formation, epoxide opening,debenzylation, and salt formation. Before addition of L-tartaric acid,the crude free-base, as a homogeneous solution in isopropylalcohol/toluene, contained 25-30% total impurities (HPLC). Afteraddition of an aqueous solution of L-tartaric acid, a thick slurryformed, and the isolated crude crystalline product contained four majorimpurities 7-10 totaling 1% (Table 1).

A reasonable hypothesis is that aniline 7 was formed by hydrolysis ofthe formamide group of 1, while 8 was generated as a result ofdehydroxylation, and compounds 9 and 10 were formed by hydrogenation ofthe starting bromohydrin 3 and amine 4, respectively, excess reactantsfrom the previous synthetic steps. After crystallization of the crudesolid from 25% aqueous isopropyl alcohol, impurities 9 and 10 wereremoved, the level of 8 decreased from 0.6% to 0.3%, and the level of 7increased from 0.1% to 0.2%. The increase in the level of 7 during thecrystallization indicated that purification of the API must berestricted to only one recrystallization of the crude wet-cake. Becausethe preceding steps in the process had been optimized, an improvement inthe purity of the final product rested solely on an improvement in theisolation and crystallization of the wet-cake and final product,respectively.

TABLE 1 Impurity Profiles of (R,R)-formoterol L-tartrate IsolatedProduct* Isolation 1 7 8 9 10 Entry (A %) (A %) (A %) (A %) (A %) 1Isolated 99.0 0.1 0.6 0.2 0.1 crude product 2 Crystallization of 99.40.2 0.3 nd nd isolated crude *Determined by HPLC analysis

After many trials it was unexpectedly discovered that when the slurry ofthe crude product was warmed to 45-50° C. for 1-5 hr, as shown in Table2, impurities 9 and 10 were completely removed, and the levels of 7 and8 were lowered to 0.04 and 0.11%, respectively. After crystallization ofthe purified crude product following this warming step, the levels of 7and 8 were easily within the required ranges: 0.12% for 7 and 0.05% for8. Although the level of 7 rose by 0.08% upon recrystallization, its lowinitial level allowed the final level to fall below 0.2%. The resultsare shown in Table 2.

TABLE 2 Impurity Profiles of (R,R)-formoterol L-tartrate IsolatedProduct* Isolation 1 7 8 9 10 Entry (A %) (A %) (A %) (A %) (A %) 1isolated 99.01 0.11 0.64 0.12 0.04 crude product 2 isolated purified99.85 0.04 0.11 nd nd crude product 3 crystallization of 99.83 0.12 0.05nd nd purified crude *Determined by HPLC analysis

The thickening of the slurry during the period at 45-50° C. suggestedthat a polymorph interconversion might have occurred during the impurityremoval. This prompted an investigation into the polymorphicmodifications of (R,R)-formoterol L-tartrate. Initial examination of themorphology of (R,R)-formoterol L-tartrate identified three distinctcrystal forms: forms A, B, and C. The polymorphs were identified atthree stages of the process: (1) the crude crystalline solid generatedafter addition of L-tartaric acid to a solution of the crude free-base(crystal form B), (2) the crystalline solid formed after warming theslurry of the crude solid to effect the impurity removal (crystal formC), and (3) the crystalline solid isolated after crystallization of thecrude wet-cake from 25% aqueous isopropyl alcohol (crystal form A).Polymorphs A and B had been observed before, and were reported in the USpatent cited above. Polymorph C had never before been observed. Usingthe protocol created for the impurity removal (vide supra), the threepolymorphs could be generated and interconverted according to Scheme II,demonstrating the concurrency of the impurity removal and polymorphinterconversion.

Addition of L-tartaric acid to the reaction solution generated from thefour step through-process protocol generated a slurry of(R,R)-formoterol L-tartrate. Filtration of the slurry, followed byrinsing the isolated white solid with isopropyl alcohol, gave themorphologically distinct crystalline solid (R,R)-formoterolL-tartrate/form B. FIG. 1 shows the IR spectrum (KBr pellet), the DSCtrace, and the X-ray powder pattern spectrum for the cystalline solid.The most distinct feature of the IR spectrum is the absorbance patternat 2400-3600 cm⁻¹, especially the triplet pattern centered at 3400 cm⁻¹.In the DSC trace, the sharpness of the endotherm peak at 177° C. isparticularly noteworthy, and in the X-ray powder diffraction spectrum,three sharp singlets and one doublet are the main features of thepattern. The solid isolated at this stage in the process provided astable crystalline white solid that could be stored for long periods(months) without decomposition.

When the resultant slurry from the through-process protocol was warmedto 45-50° C. for 1-5 hrs prior to filtration, the slurry thickened.After cooling to room temperature and filtering, a white crystallinesolid, polymorph C was isolated. FIG. 2 shows the IR spectrum (KBrpellet), the DSC trace, and the X-ray powder pattern spectrum for thiscystalline solid. A comparison of these data with the data presented inFIG. 1 clearly indicates that this solid has a unique polymorphic form.In the IR spectrum, the most readily noticeable pattern is in the2200-3800 cm⁻¹ region. The sharp peaks at approximately 3500 and 3350cm⁻¹ are characteristic of this polymorphic form and contrast sharplywith the triplet pattern shown in FIG. 1. Additionally, two very weaktransitions at 155 and 167° C. in the DSC trace contrast with the sharppeak at 177° C. shown in FIG. 1. The X-ray powder diffraction spectrumdefinitively proves that this crystalline solid is morphologicallyunique when compared to polymorph B. The pattern is characterized bythree sharp singlets and one doublet, but the shifts of these peaks areclearly different from those obtained for form B. The conversion of formB to form C was effected by warming the slurry (in the mixture ofisopropyl alcohol, water and toluene) to 45-50° C. and holding it atthat temperature.

The dependence of the process on the solvent system was studied.Generation of the crude product in crystal form B occurred by additionof an aqueous solution of L-tartaric acid to a solution of the free-basein a 3.7:1 (w/w) isopropyl alcohol:toluene solvent mixture. Afteraddition of tartaric acid, the resultant slurry consisted of a 17 wt %mixture of (R,R)-formoterol tartrate/form B in a 3.7:1.0:2.0 (w/w/w)isopropyl alcohol:toluene:water solvent mixture. The conversion of formB to form C was effected in this solvent mixture. The isolated crudesolid in crystal form B was suspended in a 1.8:1 w/w mixture ofisopropyl alcohol:water at a concentration of 17 wt %, warmed to 45-50°C., and the conversion to form C and the impurity levels were monitoredas a function of the amount of toluene in the solvent mixture (Table 3).When the slurry was warmed to 45-50° C. for an extended period, nopolymorph conversion was observed, nor was an impurity removal effected,when the amount of toluene in solution was 9 wt % or lower (entries1-3). However, when the level of toluene was raised to 13 wt %, theimpurity removal was observed (entry 4). Further analysis of this sampleshowed that conversion to crystal form C occurred also. The same resultswere observed when the level of toluene was raised to 15 wt % (entry 5).The data show that 13 wt % or more of toluene in the solvent mixture wasnecessary to cause the impurity removal and polymorph interconversion.We did not establish an upper limit, but practical considerationssuggest that, while one could accomplish the conversion and purificationwith up to 75% toluene, amounts over 15% would add to the expense ofsolvent and to the problems of disposal without affording a concomitantadvantage.

TABLE 3 Impurity Removal from Crude (R,R)-FmTA at 45° C. in 70:30 w/wIPA/Water.* Toluene Temp Time (R,R)-FmTA¹ 7¹ 8¹ Entry (wt %) (° C.) (h)(A %) (A %) (A %) 1 1 44.3 20 99.24 0.04 0.73 2 5 44.3 21 99.21 0.050.73 3 9 44.1 22 99.21 0.06 0.72 4 13 45.1 24 99.82 0.04 0.10 5 15 45.226 99.77 0.00 0.14 *FmTA concentration: 17 wt %, initially crystal formB. ¹Determined by HPLC.

Crystallization of polymorph B or polymorph C from aqueous isopropylalcohol generated the same morphologically distinct solid, polymorph A.Dissolution of either crude solid in aqueous isopropyl alcohol atelevated temperatures, followed by cooling to 0-5° C. gave thecrystallized solid. The IR spectrum, DSC trace, and X-ray powderdiffraction pattern are shown in FIG. 3. The IR spectrum ischaracterized by the broad singlet at 3420 cm⁻¹ containing twoshoulders, the singlet at 3115 cm⁻¹, and the broad nature of theabsorbances in the 2300-3500 cm⁻¹ range. The DSC shows a strong, sharpendotherm transition at 192° C., and the X-ray powder diffractionspectrum contains a unique pattern. Thus B may be converted to A eitherdirectly (by a process already described in U.S. Pat. No. 6,268,533) orB may be converted to A via C by the newly discovered process. Bothprocesses produce the same single polymorph of (R,R)-formoterolL-tartrate, uncontaminated with other polymorphic forms, but only thenew process produces the single, thermodynamically most stable polymorphof (R,R)-formoterol L-tartrate in greater than 99.5% chemical purity.

The optimized process uses a controlled manipulation of the polymorphsof (R,R)-formoterol L-tartrate as the method for providing the API with<0.2% of any single impurity and in the most thermodynamically stablecrystal form A.

Dissolution studies were done on each polymorph. A 17 wt % slurry of therespective solid in 50% aqueous isopropyl alcohol was stirred withwarming, and the temperature of dissolution was recorded. The experimentshowed that both crystal forms B and C dissolved between 49-52° C. andform A dissolved between 65-70° C. Solubility and hydrolysis inisopropyl alcohol/water mixtures were also studied. The rates ofdissolution and hydrolysis were proportional to temperature and watercontent, as expected. A successful crystallization process, therefore,requires conditions that allow for rapid dissolution and minimalhydrolysis at the lowest temperature and lowest water content possible.The process parameters are competing because higher water concentrationsallow for a lower temperature of dissolution but cause a faster rate ofhydrolysis, and lower water concentrations allow for a slower rate ofhydrolysis but require a higher temperature for dissolution. A solutionto this paradox is found in the differential solubility of the threepolymorphs.

Crystal forms B and C dissolve in aqueous isopropyl alcohol at a lowertemperature than form A, form C can be generated in higher purity thanform B, and form A is the most stable crystal form of the threepolymorphs. Taking these factors into consideration, an optimizedcrystallization process has been developed (Scheme III): (1) formationof a slurry of crude polymorph B by addition of L-tartaric acid to asolution of the free-base, (2) in-situ conversion of form B to thehighly pure form C, (3) isolation of crude polymorph C, (4) dissolutionof form C in 50% aqueous isopropyl alcohol (50-55° C.), (5) immediateseeding of the solution with form A crystals (insoluble at 55° C. in 50%aqueous isopropyl alcohol), (6) addition of isopropyl alcohol todecrease the water content to 25% and effect a rapid cooling of themixture to 40-45° C., and (7) cooling and isolation of the API,polymorph A. Implementation of this process reproducibly providespolymorph C with the level of any single impurity <0.1%. Although thelevel of 7 increases during the final crystallization (hydrolysis), theprocess provides the API with <0.2% of 7 and <0.1% of 8.

A detailed experimental procedure for the in-situ polymorphconversion/purification and crystallization processes is as follows: To460 g of a solution of the crude (R,R)-formoterol free-base in a 3.63:1(w/w) solution of isopropyl alcohol/toluene (approximately 164 g of(R,R)-formoterol free-base/L of solution) was added a solution of 40.8 gof L-tartaric acid in 237 g of water. The solution was stirred for 2 h,during which a slurry formed ((R,R)-FmTA crystal form B). The mixturewas warmed to 45-50° C. until the level of 8 was below 0.15 A % in thesolid (2-3 hr). Concomitant thickening of the slurry occurred(conversion from crystal form B to crystal form C). The mixture wascooled to 22° C., and the solid was isolated by filtration and dried togive 109 g of crude product (77% yield).

To the crude product was added 214 g of isopropyl alcohol and 272 g ofwater. The resultant slurry was warmed until dissolution occurred(50-55° C.). The solution was seeded with 1.1 g of crystals of polymorphA (1%), followed by 545 g of isopropyl alcohol to give a 25% (v/v)aqueous isopropyl alcohol solvent mixture. The solution immediatelycooled to 40-45° C. The solution was stirred for 30 min at 40-45° C.,cooled to 0° C., and stirred for 2 hr. The slurry was filtered to give93 g (85% yield) of the API as a white solid.

1-6. (canceled)
 7. A method for preventing bronchoconstriction orinducing bronchodilation in a mammal comprising administering to saidmammal a therapeutically effective amount of a highly pure(R,R)-formoterol L-tartrate comprising less than 0.5% by weight ofchemical impurities other than formoterol L-tartrate; said chemicalimpurities including less than 0.1% by weight (based on totalcrystalline solid) of a compound of formula 8: